Abstract
Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.
Highlights
Gout is the clinical manifestation of hyperuricemia which is triggered by urate precipitation in the synovial fluid of joints and other tissues [1,2]
In measurements of renal urate excretion after a purine challenge, human subjects carrying the ABCG2 transport function impairing Q141K polymorphism showed no significant differences in urate excretion and a fraction of filtered urate load (FEUA defined as the ratio between the renal clearance of uric acid to the renal clearance of creatinine), their serum urate levels were significantly elevated [40]
Only the male animals displayed elevated serum urate levels and had, in contrast to humans, at least a significantly reduced fraction of filtered urate load but again no change in urinary urate excretion [40]. These sex-related phenotypes were consistent with the increased prevalence of gout in human males [28]. The results of both human and mouse experiments suggest that the hyperuricemia induced by the ABCG2 Q141K polymorphism is not caused by a significant effect on renal urate excretion, but is likely to be triggered by different mechanism [40]
Summary
Gout is the clinical manifestation of hyperuricemia which is triggered by urate precipitation (deposition of monosodium urate crystals) in the synovial fluid of joints and other tissues [1,2]. In the pathogenesis of the disease, urate deposits promote inflammatory responses in the synovial membrane (synovitis) and arthritis characterized by sudden, severe attacks of pain, swelling, redness, and tenderness in the affected joints. Depending on the course of the disease, the symptoms of gout can occur both as acute episodic flares (gout attacks) and persist chronically and, if left untreated, can lead to irreversible deformations and impaired mobility of the affected joints [3]. Gout nephropathy, a form of chronic tubulointerstitial nephritis, induced by the deposition of urate precipitates in the distal collecting ducts and the medullary interstitium may cause progressive chronic kidney disease [4]. In addition to environmental factors, genetic predispositions leading to chronic, yet asymptomatic hyperuricemia in childhood and adolescence are considered to be the main causes for the early onset of the disease.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
